Approximately 140,000 Americans develop colorectal cancer and approximately 50,000 individuals die from the disease every year. Thus, prevention of colorectal cancer will save many Americans. Colorectal neoplasia is multifactorial in origin, and exogenous / environmental factors may cause (or prevent) specific genetic and epigenetic alterations in colorectal neoplasia. A better understanding of effects of modifiable risk factors on colorectal carcinogenesis can help optimize preventive strategies. Moreover, there appear to be important interactions between exogenous factors and tumor genetics that influence the survival of patients following a curative resection of colorectal cancer. Understanding of these potential interactions may help improve patient survival. We will utilize two large prospective cohorts, the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), which provide diet and lifestyle data over a 30-year period, long-term survival data, and paraffin-embedded tissue of colorectal cancers and adenomas. The specific aims of this proposal are: (1) to examine effects of one-carbon nutrients and alcohol on genetic and epigenetic alterations in colorectal neoplasia, and effects of these nutritional factors and tumor genetics / epigenetics on patient survival; (2) to examine effects of energy balance on molecular alterations of colorectal neoplasia and survival of patients; and (3) to examine effects of aspirin on colorectal carcinogenesis and survival of patients. Completion of these projects will improve our understanding of effects of exogenous modifiable factors on molecular alterations of colorectal neoplasia, and potential interactions of these exogenous factors and molecular alterations in tumor that may influence survival of patients after a curative resection. Accomplishment of the specific aims can help optimize preventive strategies and improve patient survival. Finally, these projects will allow me to gain invaluable experience in database analysis and epidemiologic research. I will complete courses for a Master of Science degree in Epidemiology at the Harvard School of Public Health during the first three years of the proposed award. The projects will be performed under the mentorship of Dr. Charles Fuchs, a well-established researcher in clinical oncology and epidemiology. At the completion of the projects, I will have gained the experience to become an independent researcher in cancer epidemiology.